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Personal Practice Indian Pediatrics 2001; 38: 864-871 |
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Management of Hypogammaglobulinemia |
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Correspondence to: Dr. R. Lakshman, Clinical
Research Fellow in Pediatric Immunology, University of Sheffield
and Sheffield Children’s Hospital, Sheffield, United Kingdom, S
10 2 TH. ‘Hypogammaglobulinemia’ is a term used to describe low levels of immunoglobulins (as defined by age related reference ranges) due to any cause. Primary antibody deficiency syndromes refer to conditions characterized by hypogammaglobulinemia due to genetic or unknown causes(1). They are a heterogeneous group (Table I) of conditions and lack of awareness about these conditions can lead to delays in diagnosis. While some of the more serious conditions such as X linked Agamma-globulinemia (XLA) and Common Variable Immunodeficiency (CVID) are rare, others such as selective IgA deficiency and IgG subclass deficiency are more common. Incorrect and inadequate management of patients with primary antibody deficiency syndromes can have serious long-term consequences such as bronchiectasis, poor growth and death. On the other hand prompt immunoglobulin replacement therapy may produce dramatic improvement and prevent complications(2). Diagnosis may also permit genetic counselling and early diagnosis in subsequent children. This paper discusses the clinical presentation, laboratory diagnosis and management of these conditions. Combined (T and B cell) immunodeficiencies and anti-body deficiencies secondary to malnutrition, malig-nancy, drugs, systemic disorders. congenital or acquired infections and immuno-globulin loss (protein losing gastroenteropathy or nephrotic syndrome) are not covered here. Clinical Presentation of Antibody Deficiencies Infections are a common cause of childhood illnesses and pediatric consultations. It can be difficult to differentiate clinically the child with immunodeficiency from the many children who present with ‘normal’ frequent infections. Children with normal immune systems will typically suffer 8 to 10 respiratory infections and 2 episodes of gastroenteritis per year but they recover easily and promptly, even though this means they are unwell for a significant proportion of the time. The infections they suffer are usually self-limiting and presumed to be of viral etiology. More severe infections such as pneumonia or meningitis do occur in normal children, but it would be uncommon for them to suffer recurrent serious infections. In contrast, in children with antibody deficiencies the infections are pro-longed and do not respond to ordinarily effective therapy. They also have recurrences of severe infections. Children with primary antibody deficiencies often present between 6 months and 2 years after maternal transferred antibody levels have waned. However, CVID usually presents in older children or adults. Features on history and examination that should prompt investigations for antibody deficiency are listed in Table II. Table I - Primay Antibody Deficiency Syndromes
Abbreviations: AR: Autosomal Recessive, CVID: Common Variable Immunodeficiency, THI: Transient Hypogammaglobulinemia of Infancy, SIgAD: Selective IgA Deficiency.
Investigations The investigations that may be requested in children suspected to have primary antibody deficiency syndromes are listed in Table III. The experienced clinician can be selective in his request of investigations depending on the clinical presentation. The CD 19 and CD3 levels are the most useful of the lymphocyte subsets in the diagnoses of these conditions and at the first visit they are usually requested. It is our practice to request both serum immuno-globulins and IgG subclasses as children with subclass deficiency may have normal or higher than normal levels of total serum IgG. The need to have a high index of suspicion in order not to miss cases will result in the majority of tests ordered coming back as normal. It is important to emphasize that the tests must be carried out in a laboratory experienced in performing such tests and interpreting the results. Many clinical laboratories use radial immunodiffusion for routine measurements of serum immuno-globulins and enzyme linked immunosorbent assay (ELISA) for IgG subclasses. Lately immunodiffusion kits for assay of IgG subclasses have also become available but these are not very well standardized. The radial immunodiffusion kits for serum immuno-globulins are marketed in two ranges - one for the adult range and the other more suitable for infants and children who have lower levels of immunoglobulins. It is important that when a child is being worked up for hypogamma-globulinemia, the appropriate immuno-diffusion kit is used to avoid erroneous results. These assays are time consuming and results are not available for 48 to 72 hours. For processing larger numbers of blood samples rapidly, nephelometry is the method of choice. The test results have to be compared with age related reference ranges (ideally derived from the population being tested and specific for the laboratory being used). Age related reference ranges from developing countries may be higher than those from developed countries. Results obtained from laboratories without established normal ranges for immunoglobulin levels and IgG subclass measurements may lead to unnecessary anxiety or missed diagnosis. Abnormal test results should be confirmed with a repeat test. It is also useful to remember that immunoglobulins are not the only opsonins and looking at total antibody levels and even total concentrations of specific antibodies can only give a crude estimation of opsonic function. Subtler defects in synthesis of functional antibodies and abnormalities in other opsonic factors (Mannan Binding Lectin, complement or FC(RIIA receptor), indivi-dually or in combination may result in recurrent severe infections. A collection of normal results with worrying history or phenotype should not therefore be dismissed as normal. Approach to Diagnosis The diagnosis is made by combining clinical information and results of the investi-gations. An approach to evaluating results is outlined in Table IV. Management The management varies depending on the diagnosis and the severity and frequency of infection. The goals of treatment are to improve quality of life (by the resolution of chronic infections and prevention of recurrent infections) and reduce the risk of long term complications. This is often multidisciplinary and can be helped by the involvement of an immunology nurse specialist. Acute infections that occur in spite of treatment must be managed aggressively. Recurrence of infec-tions should prompt reevaluation of current management.
Abbreviations: XLA: X linked Agammaglobulinemia, CVID: Common Variable Immunodeficiency, THI: Transient Hypogammaglobulinemia of Infancy, SIgAD: Selective IgA deficiency, DT: diphtheria and tetanus toxoid vaccines, PNC: 23 valent pneumococcal polysaccharide vaccine. Reassurance and follow up Transient Hypogammaglobulinemia of Infancy is a relatively common condition characterized by much lower levels of serum immunoglobulins than the ‘normal’ low levels seen in infants. Normal infants have a trough in their serum immunoglobulin levels at about 3 to 4 months after which the levels start increasing. In THI this trough persists and the immunoglobulin levels recover to normal only when they are about 18 to 24 months of age. The presence of normal CD 19 levels differentiates this condition from Bruton’s disease. Parents of these children must be reassured about the benign nature of the condition and have annual measurement of immunoglobulins till the condition resolves. Children found to have selective IgA or IgG subclass deficiency or specific antibody deficiency and clinically mild or infrequent infections often only need reassurance and follow up. In addition to specific measures, children with more serious antibody deficiencies must also be encouraged and helped to lead as normal a life as possible. Parents often find referral to support groups such as the Primary Immunodeficiency Association (PIA) helpful. Antimicrobial prophylaxis Many children with significant recurrent respiratory infections benefit from antibiotic prophylaxis(3). Cotrimoxazole in a once a day dose (2 mg/kg of Trimethoprim) has the advantage of good tissue penetration even in the absence of inflammation. In the United Kingdom, it is not a first line drug for use in the community and hence prevalence of organisms resistant to it is less likely. Other centers use a variety of antimicrobials including amoxycillin, coamoxiclav and azithromycin for prophylaxis. Immunoglobulin replacement This is the mainstay of management of children with XLA and CVID. Children with Hyper IgM syndrome may also need IgG replacement treatment. It is also useful in children with specific antibody deficiency or IgG subclass deficiency (usually IgG2 subclass deficiency) if they continue to suffer recurrent pyogenic infections in spite of antibiotic prophylaxis. We do not recommend IgG replacement therapy in selective IgA deficiency. Immunoglobulin replacement can be provided by the intravenous or subcutaneous route. Most of the patients with primary antibody deficiency needing antibody replace-ment at our center are on subcutaneous infusions of immunoglobulin. The main advantage of this over intravenous infusion is that the technique is simple and it is easy to teach parents to administer the treatment at home. Recent studies have shown that there are no significant differences in efficacy or adverse reaction rates between immuno-globulin replacement therapy given sub-cutaneously or intravenously(4,5). There are various immunoglobulin preparations and although efficacy is equivalent between the products there are important differences that may impinge on long term safety(6). The product used at our center is a 16% mercury- free solution (containing 800 mg in 5 ml) manufactured for intramuscular use and awaiting license for subcutaneous use. Other centers have administered preservative free 10% intravenous immunoglobulin (IVIG) subcutaneously as they did not have access to mercury free preparation manufactured for intramuscular or subcutaneous use(7). The recommended dose is between 100-200 mg/kg per week (this works out to between 12.5 and 20 ml in a 20 kg child). Quantities up to 15 ml (10 ml if the child is small or thin) can be administered into one site by means of single portable infusion pump. Two pumps can be used at different sites simultaneously for higher doses. The rate of infusion is started at 5 ml/hour per pump and gradually increased to 10 ml/h per pump over the duration of the infusion. After several uneventful infusions, the infusion may be directly started on the faster rate of 10 ml/h per pump. The infusions are given into the abdomen or thigh by means of either a butterfly needle or other special needles designed for subcutaneous use(8). Parents are trained in a hospital setting by our immunology nurse specialist to go through the steps necessary for successful infusion. Though adverse events are uncommon with subcutaneous infusion, the carers are trained in the recognition and management of allergic reactions and supplied with antihistamine syrup and intramuscular adrenaline for emergency use. Once the carers are confident of the procedure, home therapy is started and this ensures good compliance with minimum interference to life style. Some swelling and occasionally redness at the site may be seen at the end of the infusion and usually disappears within 24 hours. Some patients and parents prefer coming to the hospital every 2 to 3 weeks for intravenous immunoglobulin therapy (IVIG). Separate preparations for intravenous use are available and the usual dose is 400-600 mg per kg per dose. The infusion is commenced at a slow rate (0.5 mg/kg/minute) and doubled every 30 minutes to a maximum of 2 mg/kg/minute and is usually completed in 2 to 4 hours. Blood is collected every 3 months, prior to infusion to monitor full blood count (to identify any anemia of chronic disease), liver function and trough immunoglobulin levels. Elevated liver enzymes may suggest underlying auto-immune or viral hepatitis and require screening for viral infection (including hepatitis C) by serology and PCR. The dose of immuno-globulin is titrated so as to obtain a trough serum IgG at the upper limit of normal for age, but the dose may need to be increased further if in spite of such levels the patient continues to suffer recurrent infections, failure to thrive, chronic diarrhea or chronic lung disease. In children with IgG subclass deficiency the trough levels of the deficient IgG subclass are monitored. Adverse reactions are usually mild and if they occur routinely can be prevented by premedication with paracetamol and an anti-histamine. Intravenous hydrocortisone may be used in addition if the reactions continue to occur in spite of such premedication. However severe allergic reactions including anaphylaxis can occur and the child must be under close supervision during the infusion. Immunization Children with antibody deficiency are immunized with killed polio, diphtheria toxoid, pertussis vaccine and tetanus toxoid, Haemo-philus influenzae b vaccine and meningococcal C vaccine. They also receive pneumococcal polysaccharide vaccine as part of the functional evaluation of their immunity and this may give useful protection. Annual influenza vaccination is advised. In severe antibody deficiency such as XLA, CVID or HyperIgM syndrome, live viral vaccines such as MMR or varicella are not advised. Children with primary antibody deficiency on regular IgG treatment usually receive adequate varicella antibodies so that in most cases no special precautions are necessary in event of exposure. Bone Marrow Transplantation Patients with Hyper IgM syndrome are referred to a supraregional center for evaluation for bone marrow transplant, which may be the treatment of choice especially if a matched related donor is available and the patient is young and free of liver disease(9,10). Management of Acute Infections Acute infections in these group of children must be managed aggressively with broad spectrum antibiotics after taking necessary cultures as recurrent or prolonged infections can cause chronic damage such as bronchiectasis. Conclusions Increased awareness of primary antibody deficiency syndromes and appropriate laboratory support can lead to early diagnosis and correct management of children with recurrent infections due to these conditions. Prognosis and treatment modalities vary between the different conditions that make up this group and it is important to arrive at the correct diagnosis. Acknowledgement I am very grateful to Dr. Adam Finn, Professor of Pediatrics, Division of Child Health, University of Bristol, for checking the manuscript and making useful suggestions. I also wish to thank Jackie Hobss (Immunology Nurse Specialist) and Frank Bell (Consultant Pediatrician) for their input into this paper.
Competing interests: None stated.
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1. Chapel HM. Consensus on diagnosis and management of primary antibody deficiencies. Consensus Panel for the Diagnosis and Management of Primary Antibody Deficien-cies. BMJ 1994; 308: 581-585. 2. Skull S, Kemp A. Treatment of hypogamma-globulinemia with intravenous immunoglobu-lin, 1973-93. Arch Dis Child 1996; 74: 527-530. 3. Cunningham CK, Bonville CA, Ochs HD, Seyama K, John PA, Rotbart H, et al. Entero-viral meningoencephalitis as a complication of X-linked hyper IgM syndrome. J Pediatr 1999; 134: 584-588. 4. Smith J, Finn A. Antimicrobial prophylaxis. Arch Dis Child 1999; 80: 388-392. 5. Chapel HM, Spickett GP, Ericson D, Engl W, Eibl MM, et al. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol 2000; 20: 94-100. 6. Gaspar J, Gerritsen B, Jones A. Immuno-globulin replacement treatment by rapid subcutaneous infusion. Arch Dis Child 1998; 79: 48-51. 7. Chapel HM. Safety and availability of immunoglobulin replacement therapy in relation to potentially transmissible agents. Clin Exp Immunol 1999; 118(suppl) 1: 29-34. 8. Stiehm ER, Casillas AM, Finkelstein JZ, Gallagher KT, Groncy PM, Kobayash RH et al. Slow subcutaneous human intravenous immunoglobulin in the treatment of antibody immunodeficiency: Use of an old method with a new product. J Allergy Clin Immunol 1998; 10: 848-849. 9. Hadzic N, Pagliuca A, Rela M, Portmann B, Jones A, Veys P, et al. Correction of the hyper-IgM syndrome after liver and bone marrow transplantation. N Engl J Med 2000; 342: 320-324. 10. Kato T, Tsuge 1, Inaba J, Kato K, Matsuyama T, Kojima S. Successful bone marrow transplantation in a child with X-linked hyper-IgM syndrome. Bone Marrow Transplant 1999; 23(10): 1081-1083. |
